Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=3)[S:10][C:3]=12.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=3)[S:10][C:3]=12
Reactant: CCCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 195 °C
Yield: 85.5 %

Procedure:
To a solution of 131 (3.37 g, 12.13 mmol) in Ph2O (40 ml) was added 2-fluoro-4-nitrophenol (3.81 g, 24.26 mmol) and potassium carbonate (6.70 g, 48.52 mmol). The reaction mixture was heated to 195° C. for 20 hrs then cooled to room temperature. The residue was purified by column chromatography, eluents EtOAc/Hex (9/1 to 5/5), then MeOH/DCM (98/2), to afford title compound 132 (4.13 g, 85% yield) as a yellow solid. MS (m/z): 399.0 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([Cl:38])[CH:34]=1)[CH2:30][O:29][C:27]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:28]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
(2′-{[(3,5-Dichloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.088 g, 0.15 mmol) in THF (1 mL) and MeOH (0.8 mL) was hydrolyzed with 1N aqueous NaOH (0.5 mL) for 2.5 hours. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 571.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:16][OH:17])[C:6](=[O:11])[C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: ClCCOC1CCCCO1
Product: CC1(C)C(=O)N(CCO)c2ccc(Br)cc21

Procedure:
Prepared from 5-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:13]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.NCC(N[C@H](B1O[C@@H]2C[C@@H]3C[C@H]([C@]2(C)O1)C3(C)C)CC(C)C)=O>C(Cl)Cl>[C:4]([NH2:13])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccccc1Br
Agent: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Reaction time: 2 h
Yield: 292.9 %

Procedure:
To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 mL) were added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methyl morpholine (0.185 mL, 1.68 mmol) and 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo-N-[2-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.22 g, 78%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:17]=[C:18]([NH2:20])[S:19][CH:2]=2)=[C:6]([CH3:16])[CH:7]=1)([CH3:15])[CH3:14]
Reactant: NC(N)=S
Reactant: Cc1cc(OC(C)C)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OC(C)C)cc(C)c1-c1csc(N)n1
Yield: 72 %

Procedure:
A mixture of 2-bromo-1-(4-isopropoxy-2,6-dimethylphenyl)ethanone (5.18 g, 18.2 mmol) and thiourea (1.38 g, 18.2 mmol) in 95% EtOH (26 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isopropoxy-2,6 dimethylphenyl)thiazol-2-amine (3.44 g) as yellow solids in 72.2% yield: 1H NMR (500 MHz, CDCl3) δ 6.60 (s, 2 H), 6.26 (s, 1 H), 4.97 (s, 2 H), 4.54 (m, 1 H), 2.13 (s, 6 H), 1.32 (d, J=6.1 Hz, 6 H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C([O-])(=O)C.[NH4+]>C(O)C>[NH4+:5].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[C:3]1[C:2](=[O:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[N:5]=[C:4]1[CH3:17]
Reactant: Cc1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(C=C2C(=O)N(c3ccc(S(=O)(=O)[O-])cc3)N=C2C)c(OC)c1
Reaction time: 5 h

Procedure:
2.55 g of 5-hydroxy-3-methyl-1-(4-sulfophenyl)-1H-pyrazole, 1.83 g 2,4-dimethoxybenzaldehyde and 0.8 g of ammonium acetate in 25 mL of ethanol were heated at 70° C. After 5 hours, the mixture was cooled and filtered.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:23])([CH3:22])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][CH:7]=[C:6]([CH3:34])[CH2:5][CH2:4][CH2:3]1.CC1(C)O[O:37]1>>[CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:22])([CH3:23])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][C@@H:7]2[O:37][C@:6]2([CH3:34])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)OO1
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of desoxyepothilone B (0.0022 g, 0.0041 mmol) in CH2CI2 (0.25 mL) at −50° C. was added dimethyldioxirane (0.1 mL, 0.0095 mmol) dropwise. The resulting solution was stirred at −50° C. for 1 h. The dimethyldioxirane and solvent were removed by a stream of N2. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 1:1) gave 0.0015 g (70%) of epothiolone B (2) as a pale yellow oil which was identical with an authentic sample in 1H NMR, IR, mass spectrum, and [α]D.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C=O)C.[H-].[Na+]>[CH3:28][O:29][CH2:30][CH2:31][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1]
Reactant: COCCBr
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)n(C2CCOCC2)c2nc(-c3cnn4ccc(C#N)cc34)ncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then 2-bromoethyl methyl ether (0.032 mL, 0.34 mmol) was added and the reaction mixture was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 36 mg of the desired compound (62% yield).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH3:32][N:33]([CH2:35][CH2:36][NH2:37])[CH3:34]>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:35][CH2:36][NH:37][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:9]2[NH:10][C:11]3[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:27])[N:6]([CH2:24][CH2:25][CH3:26])[C:7]=3[N:8]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CCC)c1=O
Reactant: CN(C)CCN
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCN(C)C)cc3)nc2n(CCC)c1=O
Temperature: 0 °C
Yield: 13 %

Procedure:
A mixture of 4-(1,3-dipropyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (3.93 g, 0.01 moles) and N,N-dimethylformamide (100 ml) is prepared, cooled to 0° C., treated with thionyl chloride (2.4 g, 0.02 moles), and permitted to warm to ambient temperature with vigorous stirring. The resulting slurry is cooled to 0° C., treated with a solution of unsym dimethylethylenediamine (8.8 g, 0.10 mole) in N,N-dimethylformamide (11 ml) added in one portion, and allowed to warm to ambient temperature. The resulting solution is concentrated on a rotary evaporator. The residue is suspended in water, filtered, recrystallized from ethanol, and dried at 78° to yield 0.60 grams of N-[2-(dimethylamino)ethyl]-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesulfonamide, mp, 270°-272° C.(d).
Reaction SMILES: ClC1C=CC2N=C(NC3CCNC3)OC=2C=1.Cl.Cl[C:19]1[N:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[CH:24][CH:25]=2)[N:20]=1.C(OC([N:37]1[CH2:42][CH2:41][CH2:40][CH:39]([NH2:43])[CH2:38]1)=O)(C)(C)C>>[Cl:29][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[N:28][C:19]([NH:43][CH:39]3[CH2:40][CH2:41][CH2:42][NH:37][CH2:38]3)=[N:20]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Clc1ccc2cnc(Cl)nc2c1
Agent: Cl
Agent: Clc1ccc2nc(NC3CCNC3)oc2c1
Product: Clc1ccc2cnc(NC3CCCNC3)nc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (example 1, step 1) the title compound was prepared from 2,7-dichloro-quinazoline (Synthesis 1978, 5, 379-82) and 3-Amino-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and subsequent cleavage of the tert-butyl oxy carbonyl protecting group under acidic conditions. (MH+) 263.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][N:16](C)C=O.C(N)CN>O>[C:15]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:16]
Reactant: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Reactant: CN(C)C=O
Solvent: O
Solvent: NCCN
Product: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Reaction time: 0.5 h

Procedure:
A 19.20 g. portion of 6-(p-bromophenyl)-3(2H)-pyridazinone is mixed with 9.10 g. of cuprous cyanide in 70 ml. of dimethylformamide and stirred at reflux temperature for 12 hours. The hot mixture is poured into a solution of 46 ml. of ethylenediamine in 230 ml. of water. The mixture is stirred at ice-bath temperature for 30 minutes and the solid is separated by filtration. A second crop forms in the filtrate which is collected and added to the first crop which is then washed with water yielding 6-(p-cyanophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1>O1CCCC1>[CH3:6][CH2:7][CH2:8][CH:9]([CH3:4])[CH3:1].[Br:3][C:4]1[N:5]=[C:6]([NH:2][CH3:1])[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN
Solvent: C1CCOC1
Product: CCCC(C)C
Product: CNc1cccc(Br)n1
Yield: 8 %

Procedure:
Add a 2; M solution of methylamine in tetrahydrofuran (33.6; mL, 67.12; mmol) to 2,6-dibromopyridine (5.3; g, 22.37; mmol) and heat overnight at 110° C. in a sealed tube. Concentrate and purify by silica gel chromatography, gradient eluting from 0:100; to 20:80; ethyl acetate:iso-hexane to give the title compound (0.345; g, 8%) as a pale yellow oil which crystallizes on standing. MS (m/z): 185,187; (M+1).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[ClH:15].C(N(CC)CC)C.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44](=O)[NH:43][N:42]=2)=[CH:36][CH:35]=1>ClCCl>[ClH:15].[ClH:15].[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:41]([CH2:40][C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)=[N:42][N:43]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 210 °C
Reaction time: 4.5 h

Procedure:
In the manner described in Example 45, a mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, 1.9 ml (12.5 mmol) 4-tert-butylaniline, and 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1(2H)-phthalazinone is stirred for 4.5 h at 210° C. The frozen melt is then dissolved in dichloromethane using an ultrasonic bath, filtered off from undissolved components, and the filtrate evaporated in the RE. The oil-like residue is distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue is then stirred with 10 ml acetonitrile, filtered off from some non-transformed 4-(4-pyridylmethyl)-1(2H)-phthalazinone, and the filtrate evaporated under vacuum. Flash chromatography of the residue on silica gel with a particle size of 0.04-0.06 mm using a toluene/acetone mixture (7:3) yields a resin (free base of the title compound), which is dissolved in a mixture of 4 ml methanol and 1.5 ml of 3 N methanolic HCl. After evaporation under vacuum, recrystallization of the residue from methanol/ether, drying under HV (6 h, 80° C.), and equilibration for 16 h at 200° C. and in room atmosphere, title compound is obtained with a water content of 4.47%; m.p. 196-200° C.; ESI-MS: (M+H)+=369.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[S:18][C:19]([CH3:22])=[N:20][N:21]=3)[N:5]=2)[CH2:3][CH2:2]1.CCO.O.[Cl-].[NH4+]>ClCCl.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[S:18][C:19]([CH3:22])=[N:20][N:21]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1nnc(Cn2nc(C3CC3)c3c(N)cccc32)s1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
To a suspension of 2-((3-cyclopropyl-4-nitro-1H-indazol-1-yl)methyl)-5-methyl-1,3,4-thiadiazole (61.7 mg, 0.196 mmol) in 4:1 EtOH/H2O (2 mL) was added iron powder (0.219 g, 3.91 mmol) and ammonium chloride (10.5 mg, 0.196 mmol). The reaction mixture was heated to reflux for three hours. The reaction mixture was cooled to ambient temperature, diluted with excess dichloromethane, and the resulting suspension was dried over anhydrous sodium sulfate. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane, passed through a silica plug, eluting with 10% MeOH/DCM, and concentrated under reduced pressure to afford the product (27 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([NH:8][C:9]([C:11]2[O:12][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:30][I:31]>>[I-:31].[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:5]1([NH:8][C:9]([C:11]2[O:12][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4][CH2:3][N+:2]([CH3:30])([CH3:1])[CH2:7][CH2:6]1)[CH3:29]
Reactant: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CCN(C)CC1
Reactant: CI
Product: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CC[N+](C)(C)CC1
Product: [I-]
Yield: 98.3 %

Procedure:
Ethyl 2-(1-methyl-4-(5-(phenylethynyl)furan-2-carboxamido)piperidin-4-yl)acetate (51 mg, 0.129 mmol) was treated with MeI (80 uL, 1.29 mmol) as described in Example 2a to yield crude title compound (68 mg, 97%) which was used without further purification. 1H NMR (400 MHz, CD3OD) δ 7.57-7.53 (m, 2H), 7.47-7.42 (m, 3H), 7.21 (s, 1H), 6.87 (s, 1H), 4.11 (q, 2H, J=7.2 Hz), 3.58-3.42 (m, 4H), 3.22 (s, 3H), 3.21 (s, 3H), 3.02 (s, 2H), 2.90-2.83 (m, 2H), 2.29-2.19 (m, 2H), 1.18 (t, 3H, J=7.2 Hz); MS ESI 409.3 [M+H]+, calcd for [C24H28N2O4+H]+ 409.50.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH:29]1([N:13]([C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)[C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:35])=[O:2])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 5 h at ambient temperature to give the title compound as yellow foam. MS: m/e=455.1 [M+H+].
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21]C)=O)=[O:4]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[O:21]=[C:19]1[N:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:27])=[CH:7][C:8]=3[C:9]2=[N:16][CH:17]=[C:18]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)C)cc12)C(=O)OC
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: COC(=O)c1cnc2c3cc(NC(=O)C(C)C)ccc3ncn2c1=O
Temperature: 255 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A mixture of dimethyl [[6-(2-methylpropionamido)-4-quinazolinylamino]methylene]propanedioate (8.4 g) in diphenyl ether (42 ml) was stirred at 255° C. for 15 minutes. The reaction mixture was cooled to ambient temperature to give crystals which were filtered off, washed with hexane and dried. There were obtained 6.9 g of the crude crystals. The crude crystals were dissolved in a mixture of chloroform and methanol (4:1) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to about 150 ml. After cooling, there was obtained crystalline methyl 4-oxo-10-(2-methylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (5.85 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:14]([NH:16][CH2:17][CH2:18][CH3:19])[CH3:15]>C(O)C>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15])[C:11]=1[F:12])[C:2]#[C:3][CH3:4]
Reactant: CCCNCC
Reactant: CC#CCOc1ncnc(Cl)c1F
Solvent: CCO
Product: CC#CCOc1ncnc(N(CC)CCC)c1F
Temperature: 25 °C
Yield: 119.7 %

Procedure:
To 0.5 ml of ethanol ware added 0.1 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine and 0.11 g of N-ethylpropylamine, followed by heating under reflux for 10 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was added water and extracted three times with t-butyl methyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 6-(2-butynyloxy)-4-(N-ethylpropylamino)-5-fluoropyrimidine (the present compound (185)).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:49]=[C:48]([C:58]3[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=3)[N:47]=2)[CH2:42][CH2:41]1>CN(C=O)C>[N:43]1([C:46]2[N:51]=[C:50]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:49]=[C:48]([C:58]3[CH:64]=[CH:63][C:61]([NH:62][C:3](=[O:4])[CH:2]([F:6])[F:1])=[CH:60][CH:59]=3)[N:47]=2)[CH2:42][CH2:41][O:40][CH2:45][CH2:44]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)C(F)F
Temperature: 60 °C
Yield: 45.6 %

Procedure:
To a mixture of 2,2-difluoroacetic acid (20 mg, 0.21 mmol), HBTU (76 mg, 0.2 mmol), and DIEA (52 mg, 0.40 mmol) in 2 mL of DMF was added 4-(4,6-dimorpholino-1,3,5-triazin-2-yl) aniline (40 mg, 0.12 mmol). The reaction was stirred at 60° C. 16 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-2,2-difluoroacetamide (23 mg, 46% yield). HPLC: Rt=2.19 min; MS 421 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MH+): m/z=417.1, tR (minutes, Method G)=2.50. [α]D20=+20.64 (c=4.7 mg/mL,CHCl3)